Wednesday, 22 October 2014

Why do I think the fingolimod primary progressive trial will be positive?

Have you heard about asynchronous progressive MS hypothesis? #MSBlog #MSResearch"You may recall the post I did on a study of interferon-beta treatment in PPMS. After 2-years of treatment there was no difference between PPMSers who had been treated with IFNbeta or placebo. The investigators' concluded that interferon-beta was ineffective in PPMS. However, when these patients were reassessed at 5-years there were clear clinical and MRI features favouring interferon treatment. I suggested that in progressive MS there was a lag in the onset of action of interferon-beta. I proposed that the impact of anti-inflammatory medications in progressive MS may take several years to play out. In other words progression over the next 2 years is primed by inflammation occurring in the past. Therefore, suppressing inflammation today will have not have an impact over the next 2-years as the damage that has primed progression over the next 2 years has already occurred. In other words all anti-inflammatory therapies will have a lag in terms of showing a treatment response in progressive MS."

"This diagram illustrates the concept of the therapeutic lag. The good news is that the fingolimod PPMS or INFORMS trial is a long study with most study subjects having been followed longer than 3 years with some over 5 years. This is partly due to the design of the study, i.e. it is event driven study and the study will only be completed when enough events, or confirmed progressions occurr, to give a definitive result. This is unlike the natalizumab in SPMS, or ASCEND, trial that is only being run over 96 weeks; I personally don't think this is a long enough period of time to overcome the therapeutic lag."

"The other reason why I think the fingolimod trial in PPMS will be positive is that PPMS affects different functional systems asynchronously; i.e. my so called asynchronous progressive MS hypothesis."

"What is the asynchronous progressive hypothesis? I have made the argument in the past that the neurological systems to be affected first by progressive MS are those that have the longest, or most, wiring and hence more likely to be hit by multiple lesions; this is why the motor system to the legs, bladder and the cerebellar or balance system are typically affected first when progressive disease starts. The other systems (vision, motor system to the upper arms and face, sensory system, cognition, etc.) tend to be affected later by 'overt' progressive disease. I say overt because there is now good MRI evidence that the progressive component of MS is present from the start of the disease. The only reason we don't see it clinically is because the nervous system can compensate. However, once the compensatory systems fail progressive MS ensues. This does mean that we may have different windows of opportunity to impact on these different systems. In other words there are multiple windows of therapeutic opportunity to act and we should therefore shift our focus in PPMSers on trying to delay the onset of progression in systems that are still not clinically affected. It the fingolimod PPMS trial the the primary endpoint is the effect of fingolimod relative to placebo on delaying sustained disability progression, defined by 3 month sustained increase (>=20%) from baseline in the 25-foot timed walk test, or 9-hole peg test, or sustained increase in EDSS (0.5 or 1). The inclusion of an upper limb outcome measure makes it much more likely that this trial will be positive. In addition, the 25-foot timed walk test is also more sensitive to change than the EDSS. All these factors greatly increase the chances of the INFORMS trial being positive."

"If the INFORMS study is positive it will have halo effect and increase the use of fingolimod in SPMS as well. The other good news for MSers across the world is that fingolimod's patent expires in 2019 and as the first small molecule to come off patent will have a dramatic impact on the MS market. It means that MSers in resource poor healthcare environments will get access to a cheap licensed drug; when small molecule drugs come off-patent the price typically drops by up to 90%.""The news on the block is that Novartis will make an announcement before the end of the year regarding the outcome of the INFORMS study. My money is on the trial being positive. This would be the best news ever for PPMSers."CoI: multiple

I do think the EAE data was not going to tell us the answer however there have been reported positive data in non-autoimmune neurodegenerative models with apparent good effect.

Our data in secondary progressive EAE did not show benefit but it did in the relapsing progressive phase. I believe the people in the trial may be treated sooner rather than later in their disease course and it seems clear that relapsing progressive MSers can respond positively to this type of treatment as shown with rituximab and beta interferon.

We are a few days away from November when I was led to believe from some Pharmaceutical company people that the result would be announced.

There are rumours of the effect or non-effect that have been circulating, I wonder if they will be true or just hear say.

we will hear the take home message when the findings are announcex to the stock market. ProfG will know the answer and will be embargoed. I will be fed on mushroom food and kept in the dark until the results are announced. I predict I will eat humble pie and be happy with that.

So if this is trial is positive, does it push RRMS and PPMS much more towards being the same disease, but with different presentations during the relapsing phase (ie nothing very obvious clinically early on in PPMS)?

Would it also help support ms as being a primarily inflammatory disease with the progressive part being a secondary phenomenon to this?

Besides effect of S1P1 antagonists on heart rate, it seems that both gilenya and tysabri would have similar effects on progressive disease since they act by preventing lymphocyte entry into the CNS. Is route and frequency of administration the only difference between the two? Also, is there reason to believe that targeting T-cells alone is not enough to treat progression?

I agree with your logic but the other difference is that gilenya has more than one target it modulates S1P1 receptor to block white blood cell traffic but it is argued that S1P5 present on glial cells may have extra activity and it can accumulate in the brain.I do not believe that tysabri halts progression aswesee people taking tysabri who have progressed but does it change the rate of progression is the question that will get addressed

Thanks. This is the sort of post I like. You weigh up the positives and negatives and provide an educated guess as to what might happen. You may be wrong, but it's a lot more interesting / relevant than most research posts. Most of us live on hope - it's nice to hear your views on what's coming up and the likelihood of success.

We appreciate your kind comments, it's always nice to be appreciated and counters the negative ones we sometimes get.This blog is for you and all the other MSers out there (and their families) whose interests are paramount to us.

PML Risk Infographic

Search this Blog

Follow by Email

Subscribe To

Translate

Followers

Disclaimer

General Disclaimer: Please note that the opinions expressed here are those of the individual bloggers and do not necessarily reflect the positions of the Barts and The London School of Medicine and Dentistry, Queen Mary University of London or Barts Health NHS Trust.

Survey Disclaimer: No personal identifiers will be collected as part of these surveys. By completing these surveys you are consenting to the data you provide being analysed by Professors Giovannoni and Baker and their collaborators. Results of these surveys will be presented on this blog and may be submitted for publication.